Impact of COVID‐19 versus chronic rhinosinusitis/rhinitis associated olfactory dysfunction on health utility and quality of life

Abstract Background Olfactory dysfunction (OD) is associated with both post‐viral and inflammatory etiologies such as COVID‐19 and chronic rhinosinusitis/rhinitis (CRS/R) respectively, to result in reduced quality of life (QoL). However, the former typically induces a sudden‐onset OD while the latter has a gradual presentation. This study aims to establish and compare health utility values (HUVs) and olfactory‐specific QoL measurements between patients with COVID‐19 and CRS/R related OD. Methods This prospective study surveyed COVID‐19 and CRS/R patients with self‐reported OD using HUV assessments (EuroQol‐visual analog scale [EQ‐VAS], EuroQol‐5 dimension [EQ‐5D], time trade‐off [TTO]) and olfactory and sinonasal QoL measures (questionnaire of olfactory disorders –negative and positive statements [QOD‐NS + PS] and sino‐nasal outcome test [SNOT‐22]). A subgroup of subjects completed objective olfactory testing. Intergroup mean scores were compared using Mann–Whitney U tests. Results One hundred eleven subjects were enrolled: mean age ± SD (43.0 ± 15.4 years), 55.9% female. CRS/R was associated with lower HUVs as measured by EQ‐VAS (CRS/R: 0.67 ± 0.18 vs. COVID‐19: 0.74 ± 0.19, p = .03) and worse SNOT‐22 scores in both overall (CRS/R: 49.03 ± 21.04 vs. COVID‐19: 27.58 ± 18.45, p < .001) and subgroup analysis of objectively confirmed OD subjects (CRS/R: 52.40 ± 22.78 vs. COVID‐19: 29.84 ± 21.10, p = .01). On the other hand, COVID‐19 has greater burden on olfactory‐specific QoL (QOD‐NS + PS, COVID‐19: 23.19 ± 13.73 vs. CRS/R: 17.25 ± 11.38, p = .04). Both groups demonstrated a similar decrease in health using the EQ‐5D assessment. Conclusion CRS/R associated OD has a more severe impact on general health and sinonasal specific QoL outcomes, while COVID‐19 associated OD has a greater burden on olfactory‐specific QoL. Level of evidence Level 2c.


| INTRODUCTION
Olfactory dysfunction (OD) affects one in five adults and is associated with increased mortality and decreased quality of life (QoL). 1 Through the COVID-19 pandemic, post-viral OD associated with COVID-19 infection has become well recognized, manifesting as a profound and acute onset chemosensory loss. 2,3 The rate of persistent post-COVID OD, when defined as over 60 days of symptoms, is roughly 19% 4 and accounts for the increasing number of patients who are seeking medical help for OD. Another common cause of olfactory impairment seen in the otolaryngology clinics is inflammatory drive due to chronic rhinosinusitis (CRS) and rhinitis (R).
Although olfactory sensitivity and distorted odor perception in patients with rhinitis are often less severe than in patients with CRS, both groups (CRS/R) present with gradual onset, fluctuating olfactory symptoms, in contrast to the acute presentation of OD associated with COVID-19 infection.
Health utility values (HUVs) are self-assessed health related general QoL measurements often used by health economists to measure a person's valuation of being in a particular health state. 5 HUVs also allow for comparison of the QoL impact across different disease states, which is particularly useful in cost-utility analyses of pharmaceutical and other healthcare interventions.
Health values in CRS and in persistent OD associated with COVID-19 have been characterized in previous studies. [6][7][8] However, the HUVs associated specifically with patients with CRS/R related OD have not been described. This study aims to (1) establish HUVs in CRS/R related OD and (2) compare HUVs and olfactory and sinonasal QoL measures between patients with COVID- 19 and CRS/R related OD.

| Subject recruitment
Institutional Review Board approval by UC San Diego (UCSD) was obtained for this prospective study (IRB 191951 and IRB 200485X

| EuroQol-visual analog scale
Participants subjectively rated their own health status using a sliding scale ranging from 0 (worst imaginable health) to 100 (best health).
Each EuroQol-visual analog scale (EQ-VAS)-based health utility score was determined by dividing the selected value by 100. 9
The "EQ-5D-5L Crosswalk Index Value Calculator" was used to convert each participant's responses into a single value ranges from 0 (death) to 1 (best health possible). 9

| Time trade-off
Participants were asked "Imagine you have 20 years left to live with complete smell loss or you can give up some years to live and have complete normal smell. In your mind, living how many years with normal smell is equivalent to living 20 years with complete smell loss?" Questionnaire of OD (QOD) is a validated olfactory-specific QoL instrument used for assessment of subjective severity of OD. 12 Participants were asked 17 negative statements (NS) to assess the degree of suffering from olfactory impairment, and two positive statements (PS) to determine how well they are coping with the impairment. 12 Answer choices included four options: agree, partly agree, partly disagree, or disagree, corresponding to a score of 3 to 0 (for negative statements) or 0 to 3 (for positive statement) points, respectively. The sum of the scores for QOD-NS and QOD-PS makes the total QOD-NS + PS score with a range from 0 to 57. Higher scores indicate a stronger impairment. 12

| Sinonasal outcome test
Sinonasal outcome test (SNOT-22) is a validated CRS-specific QoL instrument with 22 questions that aim to assess the presence and severity of CRS symptoms. 13 Total SNOT-22 scores range from 0 to 110. 13 The rhinologic symptoms domain includes symptoms of decreased smell/decreased sense of taste, need to blow nose, sneezing, runny nose, thick nasal discharge, and blockage/congestion of the nose. 14

| Statistical analysis
Statistical analysis was performed with SPSS (IBM, Armork, NY) and Prism version 9.3.1 (GraphPad, San Diego, CA). Chi-squared analysis and Mann-Whitney U tests were used to compare distribution across qualitative and quantitative data, respectively.
Spearman's correlation analysis was performed to determine the relationship among different QoL measurements. Multivariate linear regression analysis was conducted to adjust for potential confounding variables, which have been reported in literature to affect QoL assessment. All tests were two-tailed and statistical significance was considered for p < .05.

| Demographics
This study prospectively recruited 111 subjects with self-reported OD: 76 (68.5%) due to COVID-19 and 35 (31.5%) due to CRS/R (Figure 1). Objective smell tests (UPSIT/BSIT) were completed by a subset of the subjects (n = 46, 41.4%). Demographic data and clinical characteristics of the participants are summarized in Table 1. Notably, the CRS/R participants were older (47.0 ± 14.0 vs. 41.1 ± 15.8, p = .03) and more frequently reported duration of OD to be >12 months (p = .04). There was no difference in gender, race, or past medical history between the two groups.

| Health utility values
Using three different measurements of health state, the measured HUVs (mean ± SD) in each group were (1) (Table 3).

| Subjective olfactory and sinonasal related quality of life assessments
Subjective smell rating via VAS method showed no significant difference in severity of smell loss between COVID- 19     28.89 ± 13.62, p = .11) ( Table 3). Comparison of mean QOD-NS + PS and SNOT-22 among subjects with quantifiably measured OD is demonstrated in Figure 5.  (Table S1).

| Spearman's correlations among quality of life instruments
Spearman correlation coefficients were calculated to further characterize the relationship between HUV measures (EQ-VAS, EQ-5D,    patients as the pandemic remains unsettled worldwide. validated. 15,18 We were unable to perform power analysis prior to the study due to the limited available data, the heterogeneity of assessment methods as well as population characteristics among published studies in the literature. Further, the recruitment of subjects from a single academic center may reflect a selection bias as those electing to participate in this study may suffer from more severe OD and/or have comorbidities.

| DISCUSSION
In conclusion, our study established HUVs associated with OD in CRS/R compared to OD in COVID-19, which could be used as baseline to assess the efficacy of therapeutic interventions in improvements in this domain. In addition, this study showed that CRS/R induced OD has a more severe impact on general health utility and sinonasal specific QoL outcomes, while COVID-19 induced OD has a greater burden on olfactory-specific QoL. Comparing QoL assessments associated with OD aids in our understanding about the aspects of QoL that are more heavily impacted by each condition, which helps guide treatment algorithms in these diseases. Further larger scale studies are needed to characterize the impact of OD severity on QoL.

CONFLICT OF INTEREST
Adam S. DeConde is a consultant for Stryker Endoscopy and receives speaker's fees for GSK.